Parkinson's disease (PD) is the second most common neurodegenerative disease with an increasing prevalence as a function of age. Although the precise cause and mechanistic dysfunctions associated with PD are not known, a progressive degeneration and loss of dopaminergic neurons in the substantia nigra is commonly observed, as are the hallmark motor deficits such as bradykinesia, tremor, rigidity, gait dysfunction and postural instability. Presently, levadopa is the standard of care for treating these symptoms; however this treatment is not curative. Prior to levadopa, compounds with anticholinergic activity represented the preferred mode of treatment for PD, however many of their undesirable side effects was believed to be a result of their non-selective antagonist activity across the spectrum of muscarinic acetylcholine receptors. Compounds possessing a more selective profile for the various muscarinic acetylcholine receptors may offer an advantage in restoring the balance between dopamine and acetylcholine in the CNS of PD patients. Along with PD, compounds modulating the muscarinic acetylcholine signaling pathways have been implicated in the treatment of diseases with similar motor symptoms such as, but not limited to, epilepsy, dystonia and fragile X syndrome.
Cholinergic neurotransmission involves the activation of nicotinic acetylcholine receptors (nAChRs) or the muscarinic acetylcholine receptors (mAChRs) by the binding of the endogenous orthosteric agonist acetylcholine (ACh). The historical use of naturally occurring anticholinergic belladonna alkaloids (atropine, scopolamine, etc.) were complicated by the presence of undesirable side effects believed to arise from their non-selective pharmacology across a variety of mAChRs. The mAChRs are widely expressed throughout the body. These mAChRs are members of the family A GPCRs and include five subtypes, designated M1-M5. M1, M3 and M5 mainly couple to Gq and activate phospholipase C whereas M2 and M4 mainly couple to Gi/o and associated effector systems. These five distinct mAChR subtypes have been identified in the mammalian central nervous system where they are prevalent and differentially expressed. M1-M5 have varying roles in cognitive, sensory, motor and autonomic functions. The M1 mAChR is found in both the central and peripheral nervous systems, particularly the cerebral cortex and sympathetic ganglia. Thus, without wishing to be bound by theory, it is believed that selective antagonists of various mAChR subtypes that regulate processes involved in neuronal motor function could prove superior to broad spectrum anticholinergics for the treatment of PD and related disorders. Based on the potential role of M1 mAChR in seizure activity and motor control, it has been postulated that highly selective M1 mAChR antagonists may have potential utility in the treatment of some epileptic disorders, as well as certain movement disorders, including PD, dystonia, and fragile X syndrome.
Evidence suggests that the most prominent adverse effects of anticholinergic agents are mediated by peripheral M2 and M3 mAChRs. Because of this, considerable effort has been focused on developing selective M1 antagonists for treatment of PD. Unfortunately, these efforts have been largely unsuccessful because of the high similarity in the orthosteric acetylcholine binding site across the mAChRs. To fully understand the physiological roles of individual mAChR subtypes and to further explore the therapeutic utility of mAChR ligands in PD and other disorders, it is important to develop compounds that are highly selective antagonists of M1 and other individual mAChR subtypes.
Despite advances in muscarinic receptor (mAChR) research, there is still a scarcity of compounds that are potent, efficacious and selective antagonists of the M1 mAChR that are also effective in the treatment of neurological disorders associated with cholinergic activity and diseases in which the muscarinic M1 receptor is involved. These needs and other needs are addressed by the present invention.